This application seeks support for the 2014 International SOX Research Conference. SRY (sex-determining region on the Y chromosome) and its 19 SOX family members (SRY-related high-mobility-group box- containing genes) encode transcription factors that preside over cell-fate determination, differentiation, and organogenesis in virtually every lineage, from embryonic stem cells to adult terminally differentiated cells. An adverse consequence of the biological centrality of SOX factors is that gain- and loss-of-function mutations in such genes underlie diverse severe human diseases. These include infertility with sex-reversal disorders (SRY, SOX9), campomelic dysplasia (skeletal malformations; SOX9), Waardenburg and Hirschsprung disease (hearing loss, hypopigmentation, aganglionic megacolon; SOX10), hypotrichosis-lymphedema-telangiectasia (sparse hair, dysfunctional lymphatic vessels, dilated blood vessels; SOX18), and multiple prevalent forms of cancer (SOX2, SOX4, SOX9, SOX11). Moreover, animal models predict that other SOX abnormalities underlie additional human birth defects and diseases, including heart, blood, lung, kidney, neuronal, skeletal and digestive diseases. Of independent translational interest, a positive corollary is that SOX2 and related genes can be used to induce pluripotent stem cells (iPS), enabling new biotechnologies to address disease through tissue repair and regeneration; applications include skeletal disorders, neurodegenerative diseases and diabetes mellitus. SOX research thus lies at the heart of many disciplines central to the missions of many NIH Institutes. SOX researchers typically attend conferences that focus on specific biological processes and diseases, but since 2005, they have also started to appreciate the benefits of a highly successful series of triennial International SOX Research Conferences. The success of this novel series relies on three unique values. First, it is the only conference that crosses disciplines through focus on SOX-specific topics. Second, to maximize world- and SOX-wide participation, each is organized in a different continent (in turn Australia, Asia, Europe and Nort America) by a leader in a different area of SOX biology. Third, the conference format, similar in spirit to Gordon Research Conferences, highlights novel, unpublished findings. Short talks, distributed between established, junior, and trainee investigators, and extended through poster sessions, allow most participants to present and discuss their work. Ample time is also given for informal discussions and mentorship activities. The 4th International SOX Research Conference will be held in Cleveland, Ohio, September 8-12, 2014. Its 4- day program will cover all major facets of SOX research, from SOX-specific functions and modes of regulation in development with application to adult physiology. Emphasis will be placed on new enabling technologies and the development of efficient strategies to prevent and cure diverse diseases. Thanks to milestone discoveries and the emergence of powerful omic approaches, SOX research has expanded exponentially in recent years. From 35 participants at the 1st conference and twice as many at the 2nd and 3rd conferences, we expect the pending 4th conference to bring together >100 researchers at all career stages, from all over the world, and representing all aspects of SOX research. Special effort is planned to welcome newcomers and continue to foster the cutting-edge, collaborative, and collegial atmosphere of this unique conference.